1. Field of the Invention
The present invention relates to labelled resiniferatoxin or labelled congeners thereof, compositions thereof, and methods of using these labelled compounds.
2. Description of Related Art
Capsaicin activates a specific class of neurons (sensory C-fiber afferent neurons) which contain tachykinins (e.g., substance P and calcitonin gene related peptide) and are involved in the perception of pain, thermoregulation, and neurogenic inflammation (Buck, S.H. and Burks, T.F., The neuropharmacology of capsaicin: review of some recent observations, Pharmacol. Rev., 38 (1986) 179-226; Holzer, P., Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides, Neuroscience, 24 (1988) 739-768.) The initial activation of the neurons is followed by long-lasting desensitization (Jancso, N., Jancso-Gabor, A. and Szolcsanyi, J., Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin, Br.J.Pharmacol.Chemother., 31 (1969) 138-151; Monsereenosurn, Y., Kongsamut, S. and Pezalla, P.D., Capsaicin- a literature survey, CRC Crit Rev.Toxicol., 10 (1982) 321-339) and capsaicin analogs have therefore been of interest as potential non-narcotic analgesics. (Maggi, C.A. and Meli, A., The sensory-efferent function of capsaicin-sensitive sensory neurons, Gen.Pharmac., 19 (1988) 1-43). The biochemical mechanism of capsaicin action remains unknown. It appears, however, that a rapid response is increased membrane conductance of cations, including Ca.sup.++, Na.sup.+, and K.sup.+16 ; inhibition of Ca.sup.++ influx either through use of Ca.sup.++ free medium (Santiciolini, P., Patacchini, R., Maggi, C.A. and Meli, A., Exposure to calcium-free medium protects sensory fibers by capsaicin desensitization, Neurosci. Lett., 80 (1987) 167-172) or by treatment with ruthenium red (Maggi, C.A., Patacchini, R., Santicoli, P., Giuliani, S., Geppetti, P. and Meli, A., Protective action of Ruthenium red toward capsaicin desensitization of sensory fibers, Neurosci. Lett., 88 (1988) 201-205) blocks the desensitization. The identification of the putative capsaicin receptors has been precluded by the lipophilicity of capsaicin and by its relatively low potency.
Recently, resiniferatoxin (RTX), a diterpene combining structural features of the phorbol ester tumor promoters and of capsaicin, has been demonstrated to function as an ultrapotent capsaicin analog (deVries, D.J. and Blumberg, P.M., Thermoregulatory effects of resiniferatoxin in the mouse: comparison with capsaicin, Life Sci., 44 (1989) 711-715; Szallasi, A. and Blumberg, P.M., Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper, Neuroscience, 30 (1989) 515-520). RTX induces pain, hypothermia, and neurogenic inflammation; the acute responses are followed by desensitization to RTX and by cross-desensitization to capsaicin (deVries, D.J. and Blumberg, P.M., Thermoregulatory effects of resiniferatoxin in the mouse: comparison with capsaicin, Life Sci., 44 (1989) 711-715; Szallasi, A. and Blumberg, P.M., Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper, Neuroscience, 30 (1989) 515-520). RTX differs from capsaicin, however, both in its potency and selectivity. RTX is 10.sup.3- 10.sup.4 fold more potent for hypothermia and neurogenic inflammation but only comparable in potency for induction of pain (Szallasi, A. and Blumberg, P.M., Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper, Neuroscience, 30 (1989) 515-520). Our in vivo findings have been recently confirmed by in vitro experiments: RTX showed potent capsaicin-like actions both on cultured sensory neurons and in the isolated spinal cord/tail preparation (Winter, J., Dray, A., Wood, J.N. and Bevan, S.J., Resiniferatoxin is a potent capsaicin-like sensory neurotoxin, Soc. Neurosci. Abstr., 18 (1989) 176.8).
Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labelled Compounds (Part A), Chapter 6, by Filer discloses the preparation and characterization of tritiated neurochemicals. Section 2, subsection 2.3 of Chapter 6 discloses catalytic dehalogenations with tritium.
"RadioTracer Techniques and Applications", Vol. 1, edited by Evans et al., Chapter 5, discloses the preparation of radiotracer compounds.
Szallasi, et al., Neuroscience, 30 (1989) 515-520 disclose that resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper.
James, et al., Molecular Pharmacology, 33: 643-649, discloses long-lasting agonist activity produced by a capsaicin-like photoaffinity probe.
deVries, et al., Life Sciences, 44: 711-715, 1989, discloses the thermoregulatory effects of resiniferatoxin in the mouse and a comparison with capsaicin.
Journal of Natural Products, May-June, 1982, Vol. 45, No. 3 by Adolf et al, discloses the structure-activity relations of polyfunctional diterpenes of the Daphnane Type, and the revised structure for resiniferatoxin and structure-activity relations of resiniferol and some of its esters.
Synthesis and Applications of Isotopically Labelled Compounds, p. 273-274, 1988, by Harris et al discloses iodine-labelled growth factors in biochemical research and receptors for platelet derived growth factor (PDGF).
Synthesis and Applications of Isotopically Labelled Compounds, pp. 267-271, by Silver discloses radioiodination techniques.